Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2

Journal of Biological Chemistry

Volumn 287, Issue 35, 2012, Pages 29579-29588

  Yuan, Minsheng ^a,b   Pino, Elizabeth ^a,b   Wu, Lianfeng ^a,b   Kacergis, Michael ^a,b   Soukas, Alexander A ^a,b  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DOMINANT NEGATIVE; GLUCOSE INTOLERANCE; GROWTH FACTOR; HEPATIC EXPRESSION; HEPATIC STEATOSIS; HIGH-FAT DIET; INSULIN RESISTANCE; LIPID METABOLISMS; LIPOGENESIS; MAMMALIAN TARGET; MAMMALIAN TARGET OF RAPAMYCIN (MTOR); PROTEIN KINASE; S6 KINASE; SERUM CHOLESTEROL;

ANTIBIOTICS; BIOCHEMISTRY; CHEMICAL ACTIVATION; DEFECTS; ENZYMES; GENE EXPRESSION; GLUCOSE; MAMMALS; PHOSPHORYLATION;

INSULIN;

GLYCOGEN SYNTHASE KINASE 3BETA; LOW DENSITY LIPOPROTEIN RECEPTOR; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MESSENGER RNA; PHOSPHATASE; PROTEIN KINASE B BETA; PROTEIN LIPIN1; PROTEIN RICTOR; S6 KINASE; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; STEROL REGULATORY ELEMENT BINDING PROTEIN 2; TRANSCRIPTION FACTOR FKHR; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DOWN REGULATION; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; FEMALE; GENE; GENE DELETION; GLUCOSE INTOLERANCE; INSULIN LIKE ACTIVITY; INSULIN RESISTANCE; INTRACELLULAR SIGNALING; LIPOGENESIS; LIVER METABOLISM; MALE; METABOLIC REGULATION; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; SREBP 1C GENE; SREBP 2 GENE;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; CHOLESTEROL; FATTY ACIDS; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION REGULATION; GLUCOSE; GLYCOGEN SYNTHASE KINASE 3; GTPASE-ACTIVATING PROTEINS; HEP G2 CELLS; HUMANS; INSULIN; INSULIN RESISTANCE; LIPOGENESIS; LIVER; MICE; MICE, TRANSGENIC; PHOSPHOPROTEINS; PHOSPHORYLATION; PROTO-ONCOGENE PROTEINS C-AKT; STEROL REGULATORY ELEMENT BINDING PROTEIN 1; STEROL REGULATORY ELEMENT BINDING PROTEIN 2; TRANS-ACTIVATORS; TRANSCRIPTION FACTORS; TUMOR SUPPRESSOR PROTEINS;

MAMMALIA; MUS;

EID: 84865503043     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M112.386854     Document Type: Article

References (41)

1. Sarbassov, D. D., Guertin, D. A., Ali, S. M., and Sabatini, D. M. (2005) Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science 307, 1098-1101
2. Guertin, D. A., Stevens, D. M., Thoreen, C. C., Burds, A. A., Kalaany, N. Y., Moffat, J., Brown, M., Fitzgerald, K. J., and Sabatini, D. M. (2006) Ablation in mice of them TORC components Raptor, Rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FoxO and PKCα, but not S6K1. Dev. Cell 11, 859-871
3. Frias, M. A., Thoreen, C. C., Jaffe, J. D., Schroder, W., Sculley, T., Carr, S. A., and Sabatini, D.M.(2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16, 1865-1870
4. García-Martinez, J. M., and Alessi, D. R. (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 416, 375-385
5. Yang, Q., Inoki, K., Ikenoue, T., and Guan, K. L. (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20, 2820-2832
6. Kumar, A., Harris, T. E., Keller, S. R., Choi, K. M., Magnuson, M. A., and Lawrence, J. C., Jr. (2008) Muscle-specific deletion of Rictor impairs insulin- stimulated glucose transport and enhances basal glycogen synthase activity. Mol. Cell. Biol. 28, 61-70
7. Kumar, A., Lawrence, J. C., Jr., Jung, D. Y., Ko, H. J., Keller, S. R., Kim, J. K., Magnuson, M. A., and Harris, T. E. (2010) Fat cell-specific ablation of Rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59, 1397-1406
8. Bentzinger, C. F., Romanino, K., Cloëtta, D., Lin, S., Mascarenhas, J. B., Oliveri, F., Xia, J., Casanova, E., Costa, C. F., Brink, M., Zorzato, F., Hall, M. N., and Rüegg, M. A. (2008) Skeletal muscle-specific ablation of Raptor, but not of Rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411-424
9. Cybulski, N., Polak, P., Auwerx, J., Rüegg, M. A., and Hall, M. N. (2009) mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc. Natl. Acad. Sci. U.S.A. 106, 9902-9907
10. Gu, Y., Lindner, J., Kumar, A., Yuan, W., and Magnuson, M. A. (2011) Rictor/mTORC2 is essential for maintaining a balance between β cell proliferation and cell size. Diabetes 60, 827-837
11. Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., and Sabatini, D. M. (2010) mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100-1104
12. Yecies, J. L., Zhang, H. H., Menon, S., Liu, S., Yecies, D., Lipovsky, A. I., Gorgun, C., Kwiatkowski, D. J., Hotamisligil, G. S., Lee, C. H., and Manning, B. D. (2011) Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and -independent pathways. Cell Metab. 14, 21-32
13. Whiteman, E. L., Cho, H., and Birnbaum, M. J. (2002) Role of Akt/protein kinase B in metabolism. Trends Endocrinol. Metab. 13, 444-451
14. Cho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., Chu, Q., Crenshaw, E. B., 3rd, Kaestner, K. H., Bartolomei, M. S., Shulman, G. I., and Birnbaum, M. J. (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292, 1728-1731
15. Leavens, K. F., Easton, R. M., Shulman, G. I., Previs, S. F., and Birnbaum, M. J. (2009) Akt2 is required for hepatic lipid accumulation in models of insulin resistance. Cell Metab. 10, 405-418
16. Ono, H., Shimano, H., Katagiri, H., Yahagi, N., Sakoda, H., Onishi, Y., Anai, M., Ogihara, T., Fujishiro, M., Viana, A. Y., Fukushima, Y., Abe, M., Shojima, N., Kikuchi, M., Yamada, N., Oka, Y., and Asano, T. (2003) Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element-binding protein involvement. Diabetes 52, 2905-2913
17. George, S., Rochford, J. J., Wolfrum, C., Gray, S. L., Schinner, S., Wilson, J. C., Soos, M. A., Murgatroyd, P. R., Williams, R. M., Acerini, C. L., Dunger, D. B., Barford, D., Umpleby, A. M., Wareham, N. J., Davies, H. A., Schafer, A. J., Stoffel, M., O'Rahilly, S., and Barroso, I. (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304, 1325-1328
18. Hussain, K., Challis, B., Rocha, N., Payne, F., Minic, M., Thompson, A., Daly, A., Scott, C., Harris, J., Smillie, B. J., Savage, D. B., Ramaswami, U., De Lonlay, P., O'Rahilly, S., Barroso, I., and Semple, R. K. (2011) An activating mutation of AKT2 and human hypoglycemia. Science 334, 474
19. Nakae, J., Kitamura, T., Silver, D. L., and Accili, D. (2001) The forkhead transcription factor FoxO1 (Fkhr) confers insulin sensitivity onto glucose- 6-phosphatase expression. J. Clin. Invest. 108, 1359-1367
20. Puigserver, P., Rhee, J., Donovan, J., Walkey, C. J., Yoon, J. C., Oriente, F., Kitamura, Y., Altomonte, J., Dong, H., Accili, D., and Spiegelman, B. M. (2003) Insulin-regulated hepatic gluconeogenesis through FoxO1- PGC-1α interaction. Nature 423, 550-555
21. Li, X., Monks, B., Ge, Q., and Birnbaum, M. J. (2007) Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator. Nature 447, 1012-1016
22. Lu, M., Wan, M., Leavens, K. F., Chu, Q., Monks, B. R., Fernandez, S., Ahima, R. S., Ueki, K., Kahn, C. R., and Birnbaum, M. J. (2012) Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and FoxO1. Nat. Med. 18, 388-395
23. Wan, M., Leavens, K. F., Saleh, D., Easton, R. M., Guertin, D. A., Peterson, T. R., Kaestner, K. H., Sabatini, D. M., and Birnbaum, M. J. (2011) Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c. Cell Metab. 14, 516-527
24. Peterson, T. R., Sengupta, S. S., Harris, T. E., Carmack, A. E., Kang, S. A., Balderas, E., Guertin, D. A., Madden, K. L., Carpenter, A. E., Finck, B. N., and Sabatini, D. M. (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408-420
25. Li, S., Brown, M. S., and Goldstein, J. L. (2010) Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc. Natl. Acad. Sci. U.S.A. 107, 3441-3446
26. Kim, J. K., Kim, Y. J., Fillmore, J. J., Chen, Y., Moore, I., Lee, J., Yuan, M., Li, Z. W., Karin, M., Perret, P., Shoelson, S. E., and Shulman, G. I. (2001) Prevention of fat-induced insulin resistance by salicylate. J. Clin. Invest. 108, 437-446
27. Chartier, C., Degryse, E., Gantzer, M., Dieterle, A., Pavirani, A., and Mehtali, M. (1996) Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli. J. Virol. 70, 4805-4810
28. Tam, B. Y., Wei, K., Rudge, J. S., Hoffman, J., Holash, J., Park, S. K., Yuan, J., Hefner, C., Chartier, C., Lee, J. S., Jiang, S., Nayak, N. R., Niyak, N. R., Kuypers, F. A., Ma, L., Sundram, U., Wu, G., Garcia, J. A., Schrier, S. L., Maher, J. J., Johnson, R. S., Yancopoulos, G. D., Mulligan, R. C., and Kuo, C. J. (2006) VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat. Med. 12, 793-800
29. Tang, E. D., Nuñez, G., Barr, F. G., and Guan, K. L. (1999) Negative regulation of the forkhead transcription factor FKHR by Akt. J. Biol. Chem. 274, 16741-16746
30. Postic, C., and Magnuson, M. A. (2000) DNA excision in liver by an albumin- Cre transgene occurs progressively with age. Genesis 26, 149-150
31. Shiota, C., Woo, J. T., Lindner, J., Shelton, K. D., and Magnuson, M. A. (2006) Multiallelic disruption of the rictor gene in mice reveals thatmTOR complex 2 is essential for fetal growth and viability. Dev. Cell 11, 583-589
32. Shimomura, I., Bashmakov, Y., and Horton, J. D. (1999) Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J. Biol. Chem. 274, 30028-30032
33. Shimomura, I., Shimano, H., Korn, B. S., Bashmakov, Y., and Horton, J. D. (1998) Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J. Biol. Chem. 273, 35299-35306
34. Alessi, D. R., Andjelkovic, M., Caudwell, B., Cron, P., Morrice, N., Cohen, P., and Hemmings, B. A. (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15, 6541-6551
35. Salih, D. A., and Brunet, A. (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr. Opin. Cell Biol. 20, 126-136
36. Altomonte, J., Richter, A., Harbaran, S., Suriawinata, J., Nakae, J., Thung, S. N., Meseck, M., Accili, D., and Dong, H. (2003) Inhibition of FoxO1 function is associated with improved fasting glycemia in diabetic mice. Am. J. Physiol. Endocrinol. Metab. 285, E718-728
37. Ikenoue, T., Inoki, K., Yang, Q., Zhou, X., and Guan, K. L. (2008) Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 27, 1919-1931
38. Porstmann, T., Santos, C. R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J. R., Chung, Y. L., and Schulze, A. (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224-236
39. Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J. H., Hsu, P. P., Bagley, A. F., Markhard, A. L., and Sabatini, D. M. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159-168
40. Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., Davis, J. G., Salmon, A. B., Richardson, A., Ahima, R. S., Guertin, D. A., Sabatini, D. M., and Baur, J. A. (2012) Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638-1643
41. Jeon, T. I., and Osborne, T. F. (2012) SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol. Metab. 23, 65-72